Behavioral Clinical Trials for Chronic Diseases: Scientific Foundations

Acknowledgments
Contents
About the Authors
Chapter 1: Introduction
	Window of Opportunity
	The Evidence: Observational Studies
	The Evidence: Intervention Studies
	Why We Wrote This Book
	Organizing Principles
		“Why Should You?” Rather Than “How To”
		Progressive Translational Science Model
		Cross-Disciplinary Methods
	The Audience
	References
Chapter 2: Quality of a Clinical Trial
	Scientific Principles
		High-Quality Evidence
		High-Quality Trials
	Challenges for Behavioral Trials
		Not Enough Phase III Behavioral Efficacy Trials
		Evidence for an “Evidence-Based” Behavioral Treatment
		Need for Progressive Science
	Overcoming These Challenges in a Behavioral Trial
		Overview of the Book
		Progression of Questions
			Link Between Stage of Development, Question, and Comparator
			Link Between Question and Outcome
			Range of Designs
		Strong Behavioral Treatments
			Progressive Development
			Hypothesized Pathway
			Clinical Significance
		Protection of Internal Validity
			Protection of Random Assignment
			Objectivity
	References
Chapter 3: Behavioral Treatment Development
	Scientific Principle
		The Drug Development Model
		Regulations Protect Consumers
		The Process of Drug Development
		General Features of the Drug Development Process
			Multidisciplinary Collaboration
			High Failure Rates
			Progressive Development
	Challenges for Behavioral Trials
		Multiple Perspectives on Behavioral Treatment Development
			Discipline-Specific Models
			Culture-Specific Models
		Consequences of Not Being Guided by a Model for Treatment Development
			Treatments Not Optimized
			Variable Standards for “Evidence Based”
			Vulnerable Patients
	Overcoming These Challenges in a Behavioral Trial
		The ORBIT Model for Developing Behavioral Treatments for Chronic Diseases
			Background
			Overview
			Discovery
				Discovery of a Significant Clinical Problem
				Discovery of a Basic Science Basis for Treatment
			The Design Phase: Phase I
				Define the Basic Elements: Phase Ia
				Refine for Strength and Efficiency: Phase Ib
			Preliminary Testing: Phase II
				Proof of Concept: Phase IIa
				Feasibility and Pilot Studies: Phase IIb
				Phase II Efficacy Trials: Phase IIc
	Selected Experience from a Behavioral Trial
		Scientific Progression in the Diabetes Prevention Program
	Recommendations
		Funding Agencies
			Dedicated Funding
			Dedicated Review Groups
			Training Opportunities
		Publication Practices
			Dedicated Journals
			Articulated Missions
		Investigators
			Pursue Scientific Progression
			Communicate Scientific Progression to Reviewers
			Pursue Foundation, Center, and Institutional Support
	Appendix
	References
Chapter 4: Hypothesized Pathway and Bias
	Scientific Principles
		The Logic of Scientific Hypotheses
			Science Proceeds by Deductive Hypothesis Testing
			Scientific Hypotheses Must Be Vulnerable to Falsification
			Tests of Scientific Hypotheses Should Be Free Of Bias
		Application of the Logic of Scientific Hypotheses
			Statistical Hypothesis Testing
			Quantification of Hypotheses
			Biases That Render a Trial Inconclusive
			Replications Determine the Worth of a Treatment
		Summary
	Challenges for Behavioral Trials
		Exploratory Aims in Confirmatory Trials
		Discipline-Specific Approach to Bias
	Overcoming These Challenges in a Behavioral Trial
		Guide Trial Design with a Hypothesized Pathway
		Interpret Trial Results with a Hypothesized Pathway
		Develop Cross-Disciplinary Sophistication in Common Trial Biases
	Selected Experience from Behavioral Trials
		The Hypothesized Pathway in a Successful Behavioral Trial
		The Hypothesized Pathway Explains a Null Trial
		Consequences of Mistaking a Failed Treatment for a Failed Hypothesis
	Recommendations
		Stick Your Neck Out
		Advance Academically as a Behavioral Trialist
		Become an Expert in Behavioral Clinical Trial Biases
	References
Chapter 5: Clinical Significance
	Scientific Principles
		Inferential Statistics
			The P-Value
			The Hypothesis Test
			The Confidence Interval
		Limitations of Inferential Statistics
			Misinterpretation
			False Security
			Ease of Manipulation
			Statistical Significance Is Not Clinical Significance
	Challenges for Behavioral Trials
		“One-Size-Fits-All” Methods
		Significance Tests Are the Status Quo
	Overcoming These Challenges in a Behavioral Trial
		Clinically Significant Treatment Target
		Clinically Significant Treatment Effect
		Clinical Significance in Sample Size Calculations
			Disaggregate the Effect Size
			Sample Size for a Phase II Efficacy Trial
			Sample Size for a Phase III Efficacy Trial
	Selected Experience from Behavioral Trials
		Clinically Significant Treatment Target from Epidemiology
		Clinically Significant Sample Size Calculation for a Phase II Efficacy Trial
		Clinical Versus Statistical Significance in Phase III Efficacy Trials
	Recommendations
		Does the Treatment Achieve a Clinically Significant Benefit?
		Does the Treatment Achieve a Better Response than a Comparator?
		What Is the Scientific Conclusion from This Trial?
		How Conclusive Is the Evidence That This Treatment Improves Health?
	References
Chapter 6: The Choice of a Comparator
	Scientific Principles
		Decision-Making Frameworks
			Implicit Rules
			Explicit Rules
			Quality-Guided Decisions
			Phase-Guided Decisions
			Purpose-Guided Decisions
			Context-Guided Decisions
			Evidence-Based Decisions
	Challenges for Behavioral Trials
		Historical Perspective
		The Status Quo
	Overcoming These Challenges in a Behavioral Trial
		The Pragmatic Model for Comparator Selection in Health-Related Behavioral Trials
			Relevant Framework (A)
			Primary Purpose of the Trial (B)
			Optimal Comparator (C)
			Significant Barriers (D)
			Significant Limitations (E)
			Finalize Choice (F)
		Purpose-Guided Comparator Choices
			Purpose of the Trial
			Purpose of the Comparator
	Selected Experience from a Behavioral Trial
		Rural Behavioral Health: Methodology Over Meaning
			Implicit Decision-Making
			Purpose-Guided Decision-Making
			Phase-Guided Decision-Making
	Recommendations
		Stalking the Elusive Dodo Bird
		What Should Investigators Do in the Meantime?
	References
Chapter 7: Feasibility and Pilot Studies
	Scientific Principles
		Terminology
		What Is Feasibility?
			Recruitment
			Trial Processes and Procedures
			Resources
			Trial Management
			Interventions and Comparators
		Inferences Based on Feasibility Data
		The Fallibility of Feasibility
		The Purposes of Pilot Studies
		Summary
	Challenges for Behavioral Trials
		Miniature Efficacy Trials
		A Wake-Up Call
		False Reassurance
	Overcoming These Challenges in a Behavioral Trial
		Credibility
		Plausibility
		Feasibility
		Are Miniature Efficacy Trials Still Justifiable?
	Selected Experience from Behavioral Trials
		A Miniature Efficacy Trial’s Short Hop
		Contemporary Trends in Pilot and Feasibility Studies
	Recommendations
		Practices That Should Be Stopped
		Practices That Should Begin
	References
Chapter 8: Protection of Random Assignment
	Scientific Principles
		History of Random Assignment
		Causal Inferences
		The Problem of Confounding
		Basic Elements of Random Assignment
			Rationale
			Process
			Limitations
			Post-Randomization Exclusions
			Intent-to-Treat Analyses
			Ethics
	Challenges for Behavioral Trials
		The Dangers of Confounding
		Tension Between Internal and External Validity
		Representative Target Populations
		Differential Treatment Demands
		Temptation of “Per-Protocol” Analyses
	Overcoming These Challenges in a Behavioral Trial
		Patient-Centered Target Populations
			Patient-Centered Eligibility
			Patient-Centered Recruitment
			Patient-Centered Consent
		Patient-Centered Retention
		Secondary “Per-Protocol” Analyses
	Selected Experience from Behavioral Trials
		Behavioral Eligibility in a Successful Behavioral Clinical Trial
		Failure to Protect Random Assignment
		The Power of “Per-Protocol” Secondary Analyses
	Recommendations
		The Primacy of a Conclusive Result
		The Target Population for a Behavioral Clinical Trial
		Attention to Retention
		Investigate Non-Adherence
	References
Chapter 9: Outcomes
	Scientific Principles
		Types of Outcomes
		Types of Trials
		Pre-Specification
	Challenges for Behavioral Trials
		Multiple Outcomes
		Subjective Outcomes in Single-Blind Designs
		Ceiling Effects
		Assessment Reactivity
	Overcoming These Challenges in a Behavioral Trial
		Single Primary Outcome
		Pre-specified Primary Outcome
		Objective Outcomes
		Patient-Reported Outcomes
		Composite Outcomes
		Minimal Clinically Important Difference
			Minimal Clinically Important Difference for Dichotomous Outcomes
			Minimal Clinically Important Difference for Continuous Outcomes
		Moderators, Mediators, and Mechanisms
			M&M’s
			Moderators
			Mediators
			Mechanisms
	Selected Experience from Behavioral Trials
		Obfuscation from M&M’s
		Ceiling Effect in a Phase III Behavioral Clinical Trial
		Questionable Value of Moderators and Mediators
	Recommendations
	References
Chapter 10: Preferences, Equipoise, and Blinding
	Scientific Principles
		Scientific Mindset
		Double-Blind Designs
	Challenges for Behavioral Trials
		Expectancy Bias
		Implications of Expectancy Bias
			Placebo Response
			Co-Intervention Bias
			Treatment Crossover/Contamination/“John Henry” Effect
			Ascertainment Bias
			Differential Dropout
	Overcoming These Challenges in a Behavioral Trial
		Belief in Equipoise
			Equipoise Is Grounded in Reality
			Equipoise Is Grounded in Ethics
		Keep Preferences Private
		Push to Extend the Blind
			Blind to Hypotheses but Not to Aims
			Neutral Names for Trial Arms
			Blind to Outcomes
			Develop a Blinding Plan
		Prevent and Detect Expectancy Bias
			Prevent and Document Crossovers and Co-interventions
			Conflict of Interest
			Independent Monitoring
			Assess the Risk of Bias
	Selected Experience from Behavioral Trials
		“Something or Nothing” in a Multi-Site Behavioral Trial
		Symptoms of Expectancy Bias in an Obesity Management Trial
		The Dream of a “True Believer”
	Recommendations
		Investigator Discipline
		Innovate to Extend the Blind
		Placebo Response: Nuisance Variable or Treatment Component?
	References
Chapter 11: The Future of Behavioral Randomized Clinical Trials
	Randomized Clinical Trials Will Not Be Outdated
		Randomized Clinical Trials Make the Strongest Causal Inferences
		Randomized Clinical Trials Can Have Strong Ecologic Validity
		Randomized Clinical Trials Are Essential to Translational Research
	Behavioral Trials Will Be More Rigorous
	Behavioral Trials Will Test Stronger Interventions
		Precision Lifestyle Medicine
			Target Subgroups Most Likely to Benefit
			Tailor Treatment to Patient Characteristics
		Multilevel Interventions
	Behavioral Trials Will Be Easier to Implement
		Behavioral Clinical Trial Networks
		Big Data in Behavioral Clinical Trials
	Behavioral Trials Will Be More Relevant
		Strategic Planning for Dissemination and Implementation
		Strategic Planning for Failure
	Summary
	References
Chapter 12: Epilogue
	References
Appendix Books on Clinical Trials
Appendix Books on Behavioral Clinical Trials
Appendix Chapter Reviewers
Index